Development and Application of a Chemical Probe Based on a Neuroprotective Flavonoid Hybrid for Target Identification Using Activity-Based Protein Profiling
Sandra Gunesch, David Soriano‐Castell, Stephanie Lamer, Andreas Schlösser, Pamela A Maher, Michael W. Decker · ACS Chemical Neuroscience · 2020
Alzheimer’s disease (AD) is the most common form of dementia, and up to now, there are no disease-modifying drugs available. Natural product hybrids based on the flavonoid taxifolin and phenolic acids have shown a promising pleiotropic neuroprotective profile in cell culture assays and even disease-modifying effects in vivo . However, the detailed mechanisms of action remain unclear. To elucidate the distinct intracellular targets of 7- O -esters of taxifolin, we present in this work the development and application of a chemical probe, 7- O -cinnamoyltaxifolin-alkyne, for target identification using activity-based protein profiling. 7- O -Cinnamoyltaxifolin-alkyne remained neuroprotective in all cell culture assays. Western blot analysis showed a comparable influence on the same intracellular pathways as that of the lead compound 7- O -cinnamoyltaxifolin, thereby confirming its suitability as a probe for target identification experiments. Affinity pulldown and MS analysis revealed adenine nucleotide translocase 1 (ANT-1) and sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) as intracellular interaction partners of 7- O -cinnamoyltaxifolin-alkyne and thus of 7- O -esters of taxifolin.